TBH the fastest approach would probably be remote controlling Excel using xlwings, because this can take advantage of Excel's optimisation. VBA might be able to hook into that as well but I've never found VBA to be fast.

Python will have to convert from XML to Python and back to XML. You've got around 5,000,000 million cells so I'd expect this to take about a minute on my machine. I'd suggest combining read-only and write-only modes to do this to keep memory use low.

If you only have numerical data (no dates) then you might be able to find a shortcut and "transplant" the relevant worksheet XML file from one Excel file to another and just alter the relevant metadata.